This invention relates to a novel taxol derivative having an antitumor activity.
Taxol is a natural compound having the following chemical structure, which can be obtained in a small amount from a trunk or the like of Taxus brevifolia. 
It is known that taxol has an antitumor activity and its action mechanism is based on the depolymerization inhibition action of microtubule during cell division, so that its clinical application is expected as an antitumor agent which is different from the general antitumor agents.
Though taxol can be obtained only in an extremely small amount from a natural source, reports have been published recently on the synthesis of taxol derivatives using a starting material 10-O-deacethylbaccatin III represented by the following structural formula: 
which is a taxol precursor that can be obtained in a relatively large amount from leaves and the like of taxaceous trees (cf. JP-A-3-505725; the term xe2x80x9cJP-Axe2x80x9d as used herein means an xe2x80x9cunexamined published Japanese patent applicationxe2x80x9d). Of such derivatives, a compound (Taxotere(trademark)) represented by the following structural formula: 
has been drawing attention as a compound which has an antitumor activity similar to or higher than that of taxol and is now under development as an antitumor agent.
Though taxol and Taxotere(trademark) are promising compounds as antitumor agents, their clinical tests have revealed that they have low efficacy-on digestive organ cancers, especially large bowel cancers, so that great concern has been directed toward the development of a derivative having more strong antitumor effects.
The 9-position of taxol derivatives is generally a keto group, but some derivatives in which this position is reduced are also known. A compound having an xcex1-configuration hydroxyl group at the 9-position has been obtained from a natural source, and various 9-position xcex1-hydroxyl group type derivatives obtained by chemical modification of the compound have been reported (for example, see J. Med. Chem., 37, 2655 (1994)). Also, it is known that a compound having a xcex2-configuration hydroxyl group at the 9-position can be synthesized chemically by reducing 10-O-deacethylbaccatin III using a reducing agent, and various 9-position xcex2-hydroxyl group type derivatives obtained by chemical modification of the compound have been reported (for example, see WO 94/20088).
As a result of extensive investigation, the inventors of the present invention have found that the antitumor activity of the aforementioned 9-position xcex2-hydroxyl group type taxol derivative sharply increases when its 9-position hydroxyl group and 10-position hydroxyl group are converted into cyclic acetal type. The present invention has been accomplished on the basis of this finding.
Accordingly, present invention relates to a compound represented by the following general formula (I) or a salt thereof: 
wherein
R1 represents a phenyl group, which may have one or more substituent(s) selected from the group consisting of a halogen atom, an alkyl group and an alkoxyl group;
R2 represents an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group or an alkoxyl group, in which these alkyl, alkenyl, alkynyl, cycloalkyl and alkoxyl groups may have one or more substituent(s) selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group, an alkoxyl group, an aryloxy group, a phenyl group, an amino group, an alkylamino group, an alkoxycarbonyl group, an an aryloxycarbonyl group, an acyl group, an acylamino group and an acyloxy group;
R3 represents a hydrogen atom, a hydroxyl group, a halogen atom, an alkoxyl group, a group xe2x80x94Oxe2x80x94R3, an acyloxy group or a group xe2x80x94Oxe2x80x94COxe2x80x94R31, in which the alkoxyl and acyloxy groups may have one or more substituent(s) selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group, a cycloalkyl group, an alkoxyl group, an aryl group, an aryloxy group, an amino group, an alkylamino group, an alkoxycarbonyl group, an aryloxycarbonyl group, an acyl group, an acylamino group, an acyloxy group and a heterocyclic group (the heterocyclic group may have one or more alkyl group(s) on the constituent atoms of its ring),
wherein R31 represents an alkylamino group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group or a heterocyclic group, in which these alkylamino, alkenyl, alkynyl, cycloalkyl, aryl and heterocyclic groups may have one or more substituent(s) selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group, an alkyl group, an alkoxyl group, an aryloxy group, a phenyl group, an amino group, an alkylamino group, an aminoalkyl group, an alkylaminoalkyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, an acyl group, an acylamino group, an acyloxy group and a nitrogen-containing heterocyclic group having a size of three- to eight-membered ring (the nitrogen-containing heterocyclic group may have one or more alkyl group(s) on the constituent atoms of its ring),
or R3 may form a three-membered ring together with the methyl group linked to a carbon atom adjacent to the carbon atom to which R3 is linked;
R4 and R5 each represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an aryl group or a heterocyclic group, in which these alkyl, alkenyl, alkynyl, aryl and heterocyclic groups may have one or more substituent(s) selected from the group consisting of an alkoxyl group, an amino group, an alkylamino group, an aminoalkyl group, an alkylaminoalkyl group and a nitrogen-containing saturated heterocyclic group having a size of five- or six-membered ring represented by the following formula: 
xe2x80x83wherein X represents an oxygen atom, a sulfur atom,
CH2, CHxe2x80x94Y, NH or Nxe2x80x94Y; in which Y is an alkyl group, (the heterocyclic group may have one or more alkyl group(s) on a carbon atom as a constituent atom of its ring), or R4 and R5 may form a thiocarbonyl group or a carbonyl group together with the carbon atom linked thereto;
Z1 represents a hydrogen atom, a hydroxyl group, a halogen atom or an alkyl group;
Z2 represents a hydrogen atom, a hydroxyl group, a halogen atom or an alkyl group;
Z3 represents an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group or a heterocyclic group, in which these alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heterocyclic groups may have one or more substituent(s) selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group, an alkyl group, an alkoxyl group, a phenyl group, an amino group, an alkylamino group, an aminoalkyl group, an alkylaminoalkyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, an acyl group, an acylamino group and an acyloxy group; and
Z4 represents an alkyl group, an aryl group or an alkoxyl group, in which these alkyl, aryl and alkoxyl groups may have one or more substituent(s) selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group, an alkyl group, an alkoxyl group, a phenyl group, an amino group, an alkylamino group, an aminoalkyl group, an alkylaminoalkyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, an acyl group, an acylamino group and an acyloxy group;
with the proviso that the dotted line of the following moiety: 
means that the corresponding bonding of the moiety may be a double bond, but R3 is not a hydroxyl group in that case.
Further, the present. invention relates to a compound having a configuration represented by the following general formula (Ia) or a salt thereof: 
wherein R1, R2, R3, R4, R5, Z1, Z2, Z3 and Z4 are as defined above.
Firstly, the terms used herein are described.
The term xe2x80x9cC1-C6xe2x80x9d as used herein means 1 to 6 carbon atoms, for example, xe2x80x9cC2-C6 alkenyl groupxe2x80x9d means an alkenyl group having 2 to 6 carbon atoms.
Each of xe2x80x9calkyl groupxe2x80x9d, xe2x80x9calkenyl groupxe2x80x9d and xe2x80x9calkynyl groupxe2x80x9d may be either straight chain or branched chain, preferably having 1 carbon atom (2 carbon atoms in the case of alkenyl and alkynyl groups) to 6 carbon atoms.
The term xe2x80x9calkoxyl groupxe2x80x9d means a group in which an alkyl group is linked to xe2x80x94Oxe2x80x94, and the alkyl group may be substituted by. a phenyl group (which may have a substituent group), such as benzyloxy, phenetyloxy, p-methoxybenzyloxy and the like groups. The alkyl moiety having 1 to 6 carbon atoms is preferred.
The term xe2x80x9calkoxycarbonyl groupxe2x80x9d means a group in which an alkyl group is linked to the oxygen atom of xe2x80x94COOxe2x80x94, and the alkyl group may substituted by a phenyl group (which may have a substituent group), such as benzyloxycarbonyl, phenetyloxycarbonyl, p-methoxybenzyloxycarbonyl and the like groups. The alkyl moiety having 1 to 6 carbon atoms is preferred.
The term xe2x80x9caryl groupxe2x80x9d means a monovalent group in which one hydrogen atom is removed from the nucleus of an aromatic hydrocarbon, such as phenyl, tolyl, biphenyl, naphthyl and the like groups.
In the xe2x80x9caminoalkyl groupxe2x80x9d, an amino group may be bonded at any position of an alkyl group, and the alkyl group preferably have 1 to 6 carbon atoms.
The term xe2x80x9calkylamino groupxe2x80x9d means a group in which an amino group is substituted by one alkyl group or a group in which amino group is substituted by two alkyl groups (the two alkyl groups may be the same or different from each other). The alkyl group moiety preferably have 1 to 6 carbon atoms.
The term xe2x80x9cacyl groupxe2x80x9d means a group in which a hydrogen atom, an alkyl group or an aryl group is linked to a carbonyl group (xe2x80x94COxe2x80x94), such as formyl, acetyl, propanoyl, benzoyl and the like groups. In this case, the alkyl group to be linked have preferably 1 to 6 carbon atoms, and a phenyl group is preferred as the aryl group to be linked.
The term xe2x80x9cheterocyclic groupxe2x80x9d means a substituent group which has one or a plurality of at least one atom selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom and is derived from a monocyclic or bicyclic saturated or unsaturated heterocyclic compound, and these heterocyclic groups may be linked at any position. Examples of the monocyclic heterocyclic group include substituent groups derived from monocyclic heterocyclic compounds such as pyrrole, furan, thiophene, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, imidazole, pyrazole, imidazolidine, pyrazolidine, oxazole, thiazole, oxadiazole, thiadiazole, pyridine, dihydropyridine, tetrahydropyran, piperidine, pyridazine, pyrimidine, pyrazine, piperazine, dioxane, pyran, morpholine and the like. Examples of the bicyclic.heterocyclic group include substituent groups derived from bicyclic heterocyclic compounds such as benzofuran, indolizine, benzothiophene, indole, naphthylidine, quinoxaline, quinazoline, chroman and the like.
The term xe2x80x9cnitrogen-containing heterocyclic groupxe2x80x9d means a substituent group derived from a saturated or unsaturated heterocyclic compound which always has one nitrogen atom as a constituent atom of the heterocyclic group and may also have one or a plurality of atom selected from an oxygen atom, a nitrogen atom and a sulfur atom as other constituent atoms. Examples of such group include pyrrole, pyrrolidine, imidazole, pyrazole, imidazolidine, pyrazolidine, oxazole, thiazole, oxadiazole, thiadiazole, pyridine, dihydropyridine, piperidine, pyridazine, pyrimidine, pyrazine, piperazine, morpholine, thiomorpholine and the like.
The xe2x80x9cnitrogen-containing saturated heterocyclic group having a size of five- or six-membered ring represented by the following formula: 
wherein X represents an oxygen atom, a sulfur atom, CH2, CHxe2x80x94Y, NH or Nxe2x80x94Y, in which Y is an alkyl group, (the heterocyclic group may have one or more alkyl group(s) on carbon atoms as constituent atoms of its ring)xe2x80x9d means a substituent group derived from a saturated heterocyclic compound which always has one nitrogen atom as a constituent atom of the heterocyclic group and has a size of five- or six-membered ring, and its examples include pyrrolidine, imidazolidine, pyrazolidine, oxazolidine, thiazolidine, isooxazolidine, isothiazolidine, piperidine, piperazine, morpholine, thiomorpholine and the like.
The term xe2x80x9cR3 may form a three-membered ring together with the methyl group linked to a carbon atom adjacent to the carbon atom to which R3 is linkedxe2x80x9d means that the 7- and 8-position moieties form the following structure. 
Next, each substituent group in the general formula (I) is described.
Preferred examples of the xe2x80x9calkyl groupxe2x80x9d and xe2x80x9calkoxyl groupxe2x80x9d as substituent groups of the phenyl group of R1 are those which have 1 to 3 carbon atoms.
The number of substituent groups of the phenyl group of R1 is preferably 1 or 2, and the substituent group is substituted preferably at the meta position.
Unsubstituted phenyl group is preferred as R1. Also preferred is a phenyl group having 1 or 2 fluorine atoms, chlorine atoms, methyl groups or methoxy groups substituted at the meta position.
As R2, an alkyl group, an alkoxyl group and a cycloalkyl group are preferred.
As the xe2x80x9calkyl groupxe2x80x9d of R2, a C1-C6 alkyl group is preferred, and a methyl group, an ethyl group and a propyl group are particularly preferred.
As the xe2x80x9calkoxyl groupxe2x80x9d of R21, a C1-C6 alkoxyl group is preferred, and a methoxy group and an ethoxy group are particularly preferred.
As the xe2x80x9ccycloalkyl groupxe2x80x9d of R2, a C3-C6 cycloalkyl group is preferred, and a cyclopropyl group is particularly preferred.
As R2, a methyl group, an ethyl group, a propyl group, a methoxy group, an ethoxy group or a cyclopropyl group is particularly preferred.
As the xe2x80x9chalogen atomxe2x80x9d of R31, a fluorine atom is preferred.
As R3, a hydrogen atom, a fluorine atom or a hydroxyl group is particularly preferred. Also preferred as R3 is a group in which a three-membered ring is formed together with the methyl group linked to a carbon atom (8-position) adjacent to the carbon atom (7-position) to which R3 is linked, namely a group in which the 7- and 8-position moieties have the following structure. 
As the alkyl groups of R4 and R5, those having 1 to 6 carbon atoms are preferred, and a methyl group, an ethyl group and a propyl group are particularly preferred.
As the alkenyl group of R4 and R5, those having 2 to 6 carbon atoms are preferred, and allyl group is particularly preferred.
As the substituent group of the alkyl, alkenyl or phenyl group of R4 and R5, an amino group, an alkylamino group or a nitrogen-containing saturated heterocyclic group having a size of five- or six-membered ring represented by the following formula: 
wherein X represents an oxygen atom, a sulfur atom, CH2, CHxe2x80x94Y, NH or Nxe2x80x94Y, in which Y is an alkyl group, (the heterocyclic group may have one or more alkyl group(s) on a carbon atom as a constituent atom of its ring) is preferred.
The alkyl moiety of the alkylamino group is preferably a C1-C3 alkyl group, and it may be a dialkyl substitution (in the case of dialkyl substitution, the two alkyl groups may be the same or different from each other).
As the nitrogen-containing saturated heterocyclic group having a size of five- or six-membered ring represented by the following formula: 
(the heterocyclic group may have one or more alkyl group(s) on a carbon atom as a constituent atom of its ring), groups derived from piperazine, morpholine, thiomorpholine, 4-C1-C3 alkylpiperazine are particularly preferred.
Also, methyl group is preferred as the alkyl group to be substituted on the carbon atom as a constituent atom of the ring of heterocyclic group.
A preferred example as R4 and R5 is a combination in which one is a hydrogen atom or an alkyl group and the other is an alkyl group, an alkenyl group or a phenyl group.
As the xe2x80x9chalogen atomxe2x80x9d of Z1 and Z21 a fluorine atom, a chlorine atom and a bromine atom are preferred.
As the xe2x80x9calkyl groupxe2x80x9d of Z1 and Z2, a methyl group, an ethyl group and a propyl group are preferred.
As Z1, a halogen atom and a hydroxyl group are preferred, and a fluorine atom is particularly preferred as the halogen atom.
As Z2, a halogen atom, a hydrogen atom or an alkyl group is preferred, in which a fluorine atom is particularly preferred as the halogen atom, and a methyl group is particularly preferred as the alkyl group.
Most preferred examples as Z1 and Z2 include a combination in which Z1 is a fluorine atom and Z2 is a fluorine atom, a combination in which Z1 is a hydroxyl group and Z2 is a hydrogen atom and a combination in which Z1 is a hydroxyl group and Z2 is a methyl group.
As Z3, an aryl group, a heterocyclic group and an alkenyl group are preferred.
As the xe2x80x9caryl groupxe2x80x9d of Z3, a phenyl group is preferred.
As the xe2x80x9calkenyl groupxe2x80x9d of Z3, 2-methyl-1-propenyl is preferred.
As the heterocyclic group of Z31, a monocyclic heterocyclic group is preferred, more preferably a monocyclic five- or six-membered ring heterocyclic group, such as pyrrole, furan, thiophene, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, imidazole, pyrazole, imidazolidine, pyrazolidine, oxazole, thiazole, oxadiazole, thiadiazole, pyridine, dihydropyridine, tetrahydropyran, piperidine, pyridazine, pyrimidine, pyrazine, piperazine, dioxane, pyran, morpholine and the like.
Among the heterocyclic group of Z3, a monocyclic five- or six-membered ring heterocyclic group having one oxygen atom, nitrogen atom or sulfur atom as a constituent atom of the ring structure is more preferred, and examples of such group include those which are derived from pyrrole, furan, thiophene, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, pyridine, dihydropyridine, tetrahydropyran, piperidine, pyran and the like.
Among the heterocyclic group of Z3, a monocyclic five- or six-membered ring unsaturated heterocyclic group having one oxygen atom, nitrogen atom or sulfur atom as a constituent atom of the ring structure is most preferred, and examples of such group include those which are derived from furan, pyridine and pyrrole.
As Z3, a 2-methyl-1-propenyl group, a phenyl group, a furyl group, a pyridyl group and a pyrrolyl group are particularly preferred.
As Z4, an aryl group or an alkoxyl group is preferred.
As the xe2x80x9caryl groupxe2x80x9d of Z4, a phenyl group is preferred.
As the xe2x80x9calkoxyl groupxe2x80x9d of Z4, a tert-butoxy group is preferred.
As Z4, a phenyl group and a tert-butoxy group are particularly preferred.
Preferably, the compound of the present invention may have the following configuration. 
Configuration of the 3xe2x80x2-position, to which the substituent group Z3 is linked, may be either of the two configurations, but preferably the same configuration of natural taxol. Also, configuration of the 7-position is either xcex1- or xcex2-configuration.
The taxol derivative of the present invention may be in the free form as such and in the form of an acid addition salt or a salt of carboxylic acid. Examples of the acid addition salt include inorganic acid salts such as hydrochloride, sulfate, nitrate, hydrobromate, hydroiodate, phosphate and the like and organic acid salts such as acetate, methanesulfonate, benzenesulfonate, toluenesulfonate, citrate, maleate, fumarate, lactate and the like.
Examples of the salt of carboxyl group may be either inorganic salts or organic salts, which include alkali metal salts such as lithium salt, sodium salt, potassium salt and the like, alkaline earth metal salts such as magnesium salt, calcium salt and the like, as well as ammonium salt, triethylamine salt, N-methylglucamine salt, tris-(hydroxymethyl)aminomethane salt and the like.
The following describes production process of the compound of the present invention. In the practice of the reaction, the substituent groups may be protected with. protecting groups if desired, and conversion sequence of each substituent group is not particularly limited. 
In the above reaction scheme, R13 means R3 itself or R3 protected by a protecting group (when R3 is substituted by a hydroxyl group, an amino group or the like or when R3 is a hydroxyl group);
R24 means R4 itself or R4 protected by a protecting group (when R4 is substituted by an amino group or the like);
R15 means R5 itself or R5 protected by a protecting group (when R5 is substituted by an amino group or the like);
Z11 means Z1 itself or Z1 protected by a protecting group (when Z1 is a hydroxyl group);
Z21 means Z2 itself or Z2 protected by a protecting group (when Z2 is a hydroxyl group);
Z31 means Z3 itself or Z3 protected by a protecting group (when Z3 is substituted by a hydroxyl group, an amino group or the like); and
Z41 means Z4 itself or Z4 protected by a protecting group (when Z4 is substituted by a hydroxyl group, amino group or the like).
R8 and R9 are independently a hydrogen atom, an alkyl group, an aryl group and the like and, in a preferred combination, both are methyl groups or one is a p-methoxyphenyl group and the other is a hydrogen atom.
R10 and R11 are protecting groups of the hydroxyl group.
A compound (3) is obtained by allowing a compound (2) derived from 10-O-deacetylbaccatin III (a compound (1)) to react with an aldehyde or ketone represented by R14C(xe2x95x90O)R15 or an acetal represented by R14R15C(OR45)2 (R45 is methyl or the like alkyl group) in the presence of an acid catalyst such as 10-camphorsulfonic acid, p-toluenesulfonic acid or the like. Next, a compound (4) is obtained by condensing the 13-position hydroxyl group of the compound (3) with a compound (A), (B) or (C) in accordance with respective ordinary method already reported.
As the condensation reaction with the compound (A) or (B), a method is known in which a carboxylic acid activating agent such as di(2-pyridyl) carbonate or dicyclohexylcarbodiimide is used in the presence of 4-dimethylaminopyridine or the like base catalyst. In this connection, when the compound (A) is used, Z11 and Z21 become a combination of hydrogen atom-and hydroxyl group.
As the condensation reaction with the compound (C), a method is known in which sodium hexamethyldisilazide or the like base is used.
At this stage of reaction, the compound (A), (B) or (C) will react with the 7-position hydroxyl group of compound (3) in some cases. In that case, the product of interest can be separated and purified by a silica gel column chromatography or the like means. Alternatively, since a compound (5) in which a protecting group is introduced selectively into the 7-position of compound (3) can be obtained by selecting proper protecting group and reaction conditions (a high selectivity is obtained especially in the case of a carbamate type protecting group, for example, the 7-position can be selectively protected with 2,2,2-trichloroethoxycarbonyl group by carrying out the reaction with 2,2,2-trichloroethoxycarbonyl chloride in pyridine at 0xc2x0 C.), the compound (4) may be synthesized by condensing the 13-position hydroxyl group of this compound (5) with the compound (A), (B) or (C) in the same manner as described above. The compound (5) can also be obtained by another method in which the 13-position hydroxyl group of compound (3) is converted into ketone using manganese dioxide or the like oxidizing agent, a protecting group is introduced into the 7-position hydroxyl group of the resulting compound to obtain a compound (6), followed by reducing the 13-position ketone again into hydroxyl group using a sodium borohydride or the like reducing agent.
After conversion or deprotection of each substituent group of the thus obtained compound (4) as occasion demands, the compound. (I) of interest can be obtained by converting the 2-position benzoyl group into COR1, the 4-position acetyl group into COR2 the 7-position hydroxyl group into R3, and the R14, R15, Z11, Z21, Z31 and Z41 into R4, R5, Z1, Z2, Z3 and Z4, respectively. Such conversion and deprotection can be carried out by using general techniques of organic chemistry, such as the following examples.
Conversion of the 2-position benzoyl group into COR1 can be effected, for example, in accordance with a method described in a literature (Tetrahedron Letter, 35, 8931 (1994)) in which the 2-position ester bond is selectively hydrolyzed and then acylated, by which a compound whose R1 is other than a phenyl group is obtained.
Conversion of the 4-position acetyl group into COR2 can be effected, for example, in accordance with a method in which a reaction with a compound represented by R21xe2x80x94X (R21 represents an alkyl group, an alkenyl group or an aryl group and X represents a halogen atom such as iodine atom, bromine atom or the like or a leaving group such as methanesulfonyl group, p-toluenesulfonyl group or the like) is carried out in the presence of sodium hexamethyldisilazide or the like base at a temperature of from xe2x88x92100xc2x0 C. to room temperature, thereby obtaining a compound whose R2 is other than a methyl group.
The compound whose R2 is other than a methyl group can also be obtained by allowing the compound (6) to react with the compound represented by R21xe2x80x94X in the presence of sodium hexamethyldisilazide or the like base to obtain a compound in which the 4-position acetyl group is converted into COR2, subsequently reducing the 13-position hydroxyl group and finally carrying out condensation reaction with the compound (A), (B) or (C).
Conversion of the 7-position hydroxyl group into R3 can be effected by various methods depending on the type of R3. A compound in which R3 is hydrogen can be obtained by removing the 7-position hydroxyl group by a known method (for example, see J. Org. Chem., 58, 5028 (1993)). A compound in which R3 is xe2x80x94OC(xe2x95x90O)R31 can be obtained by acylating the 7-position hydroxyl group using a carboxylic acid or an acid chloride based on general techniques of organic chemistry. A compound in which R3 is xe2x80x94OC(xe2x95x90O)NQ1Q2 (Q1 and Q2 are independently a hydrogen atom or an alkyl group) can be obtained by a method in which the 7-position hydroxyl group is allowed to react with a compound represented by ClC(xe2x95x90O)OR32 (R32 is p-nitropheyl or the like aryl group) and then with an amine, to react with phosgene in the presence of an amine, to react with a compound represented by ClC(xe2x95x90O)NQ1Q2 (Q1 and Q2 are independently a hydrogen atom or an alkyl group) or to react with an isocyanate represented by R31Nxe2x95x90Cxe2x95x90O. Conversion into R3 of interest can also be made by converting the 7-position hydroxyl group and then carrying out several steps of organochemical conversion.
In another process, a compound (9) is obtained by protecting the 13-position hydroxyl group of compound (5) with a protecting group R11 which can be distinguished from the protecting group R10, removing R10 to obtain a compound (8), converting-the 7-position hydroxyl group of compound (8) into R13 in the same manner as described in the foregoing and then removing the protecting group R11. Thereafter, the 13-position hydroxyl group of compound (9) is condensed with the compound (A), (B) or (C), and then conversion and deprotection of various substituent groups are carried out to obtain the compound (I) of interest. In this connection, the compound (8) can be synthesized directly from the compound (3) by selecting proper protecting group R11 and reaction conditions, and the compound (9) can also be synthesized directly from the compound (3) by conversion of the 7-position hydroxyl group.
A compound of interest whose R3 is a halogen atom, for example, a compound whose R3 is fluorine atom, can be obtained by treating a compound having a hydroxyl group at the 7-position with diethylaminosulfur trifluoride in tetrahydrofuran, methylene chloride, ethyl ether, toluene, 1,1-dimethoxyethane or a mixture solvent thereof.
The compound (8) can also be synthesized from a compound (D) which is obtained-from the compound (1). That is, the 13-position hydroxyl group of compound (D) is protected with the protecting group R11 which can be distinguished from 2,2,2-trichloroethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl groups at the 7- and 10-positions are removed, and then the thus obtained compound is treated with a reducing agent such as tetrabutylammonium borohydride or the like to convert the 9-position ketone into hydroxyl group and allowed to react with an aldehyde, a ketone or an acetal in the same manner as described in the foregoing, thereby obtaining the compound (8).
The following compounds as the production materials can be synthesized by reported methods.
Compound (2): WO 94/20088 and others.
Compound (D): Tetrahedron, 422, 4451 (1986) and others.
Compound (A): Tetrahedron Letter, 33, 5185 (1992) and others.
Compound (B): J. Am. Chem. Soc., 110, 5917 (1988) and others.
Compound (C): Tetrahedron Letter, 34, 4149 (1993) and others.
In the above synthesis methods, compounds in which the 7-position has xcex2-configuration are obtained in general. Since it is known that configuration of the 7-position hydroxyl group is isomerized from to a when a taxol derivative in which the 9-position is keto group and the 7-position is not protected is treated with a base, a compound having a-configuration at the 7-position can be synthesized by reducing the 9-position keto group into a hydroxyl group after isomerization.
The compound of the present invention can be used for the treatment of various cancers such as lung cancers, digestive organ cancers, ovarial cancers, uterine cancers, breast cancers, cancers of liver, head and neck cancers, blood cancers, renal cancers, testicular tumors and the like.
The compound of the present invention can be administered as intravenous, intramuscular, subcutaneous and the like various injections or through other various routes of administration such as oral administration, percutaneous absorption and the like. Of these methods, intravenous injection by a solutions and oral administration are desirable. The solutions can be prepared by forming an acid addition with a pharmacologically acceptable acid or an alkali metal salt with sodium or the like. In the case of oral administration, the compound may be in its free form or a salt form.
Appropriate pharmaceutical preparation is selected corresponding to each administration method and prepared by usually used preparation method. Of the dosage forms of the antitumor agent of the present invention, examples of oral preparations include tablets, powders, granules, capsules, solutions, syrups, elixirs, oil or aqueous suspensions and the like. In the case of injections, stabilizing agents, antiseptics, solubilizing agents and the like may be used in the preparation. The injections which may contain these auxiliary agents may be dispensed into containers and made into solid preparations by freeze-drying or the like means to be dissolved again before using.
Liquid preparations include solutions, suspensions, emulsions and the like, and suspending agents, emulsifying agents and the like may be used as additives when these preparations are prepared.
The compound of the present invention can be used for the treatment of cancers in mammals, particularly in human. In the case of human, it may preferably be administered once a day repeatedly at appropriate intervals.
It may be administered in a dose of from about 0.5 to 50 mg, preferably from about 1 to 20 mg, per 1 m2 of the body surface area.